Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs, probably due to their therapeutic properties as anti-inflammatories, analgesics, anti-pyretics, and anti-thrombolics and are used to treat a variety of clinical conditions manifesting such symptoms as pain, inflammation, fever, and to treat and prevent atherosclerosis.
While these drugs are highly effective, oral administration of many NSAIDs can cause serious adverse effects such as gastrointestinal bleeding and ulceration, liver and kidney damages, and central nervous system and cutaneous disturbances, particularly after extended use. Therefore, in an effort to minimize the adverse effects associated with oral administration, non-oral delivery of NSAIDs has been extensively investigated in recent years.
Transdermal delivery, in particular, is an attractive option because it avoids the hepatic first-pass metabolism, reduces the side effects associated with oral administration, is associated with higher patient compliance and, in some cases, enhances therapeutic efficacy of the drug.
Transdermal delivery of NSAIDs is particularly useful for treatment of rheumatoid arthritis and related conditions, which are characterized by painful and swollen joints due to inflammation in the musculoskeletal tissues of the joints. However, although topical administration of certain NSAIDs has been shown to deliver the drug to the local musculoskeletal tissues of joints where arthritic conditions often develop, due to the low solubility of NSAIDs in water, the effectiveness of topical administration of NSAIDs is limited by the inability of these drugs to permeate the skin.
NSAIDs are weak acid. There are roughly nine major classes of NSAIDs, which are salicylate derivatives (such as acetosalicylate [aspirin]), propionic acid derivatives (such as ibuprofen), aniline derivatives (such as aminophenolacetaminophen [tylenol]), pyrazole derivatives (such as phenylbutazone), N-arylanthranilic acid (or fenamates) derivatives (such as meclofenamate), indole derivatives (such as indomethacin), acetic acid derivatives (such as diclofenac), oxicam derivatives (such as piroxicam), and miscellaneous others (such as celecoxib).
Among the NSAIDs, diclofenac, which is 2-(2,6-dichloro-anilino)-phenyl-acetic acid, is particularly known for its role as an anti-rheumatic agent for treatment of rheumatoid arthritis. Diclofenac belongs to the acetic acid class of NSAID. Due to its relatively low solubility in water, an aqueous injection solution of diclofenac is difficult to achieve.
U.S. Pat. No. 4,711,906 discloses a liquid diclofenac preparation where a better dissolution of the diclofenac is obtained when a local anesthetic, lidocaine, is added. This liquid diclofenac preparation is particularly suitable for use as injection solution.
Another NSAID similar to diclofenac and also belongs to the acetic acid class of NSAIDs is ketorolac. Ketorolac is comparable to opioids in terms of providing pain relief. For example, the overall analgesic effect of 30 mg of ketorolac is equivalent to that of 6 to 12 mg of Morphine.
Ketorolac is (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid. It is a derivative of pyrrolizine carboxylic acid and is structurally related to tolmetin and zomepirac. Like diclofenac, the free acid form of ketorolac has very low solubility in water. The most commonly used salt form of ketorolac is ketorolac tromethamine, which is much more water soluble than the free acid form of ketorolac.
Although NSAIDs are widely used as anti-inflammatories and analgesics, the use of NSAIDs in alleviating symptoms associated with herpes virus infection is largely unexplored. Herpetic infections are highly contagious skin eruptions or lesions, characterized by a cluster of small blisters or watery vesicles. The lesions are caused by an acute viral infection. The virus is from the genus Herpesvirus. 
The herpesviruses comprise a large family of double stranded DNA viruses. The herpesvirus family can be divided into three subfamilies (i.e., α, β, and γ) based upon a number of biological properties such as host range and tropism, viral life cycle, and viral persistence and latency. Eight of the herpesviruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and HHV-8), have been shown to infect humans.
Among the herpesviruses, the two commonly known viruses are herpes simplex virus types 1 and 2, referred to as HSV1 and HSV2 and varicella-zoster virus (VZV). HSV1 causes orofacial lesions, commonly known as fever blisters or cold sores. These lesions most commonly appear on the lips, but may appear on the face, in the mucous membrane lining of the oral cavity, in the eye and nose, and occasionally on the trunk of hands. Infections of the mouth are designated with the term herpes labialis, also called cold sore (feverblister). Other parts of the face can also be affected and the infections thereof are referred to as facial herpes simplex. The infection can also manifest itself on other parts of the body. Approximately 30% of the United States population suffer from recurrent episodes of HSV1. HSV2, which is less common than HSV1, causes genital lesions. Conversely, genital herpes is caused in about 30% of cases by HSV1.
Varicella-zoster virus (VZV) causes varicella, commonly known as chicken pox, and herpes zoster, commonly known as shingles. Shingles affects the skin and nerves and is characterized by groups of small blisters or lesions appearing along certain nerve segments. The lesions are most often seen on the back and may be preceded by a dull ache in the affected site.
Once an individual has been infected with the herpes virus, the virus will thereafter remain latently in the body. In latent state, the virus is situated in nerve cell bodies in the ganglia. Due to particular stimuli, such as influenza infection, other respiratory disorders, gastrointestinal infections, stress, fatigue, menstruation, pregnancy, allergy, sunlight, or fever, the latent virus can be activated and travel from the ganglia along the well-defined nerve paths to the skin surface and there multiply and cause the symptoms.
There is no treatment known to kill the herpes virus at this time. Most of the available treatments can only help to accelerate the healing of the lesions and the associated symptoms, but have not been shown to be efficacious in the treatment of herpes virus infections.
The best known treatment for herpes virus infections at this time is probably Zovirax.RTM. Ointment (Glaxo Wellcome), which contains the active ingredient acyclovir. Acyclovir, 9-(2-hydroxyethoxymethyl), is a purine nucleoside analogue targeting viral encoded DNA polymerase. Other purine nucleoside analogues which are commercially available for treating herpes virus infections include ganciclovir (Roche) and foscarnet (Astra). Although effective, these purine nucleoside analogues are poorly soluble in water and demonstrate low bioavailability. These, accompanying the relative long recovery time required (i.e., generally takes longer than 2 weeks for patients to recover) and high prescription cost, make the drugs less attractive to the patients.
Other commonly known anti-viral drugs for treatment of herpes virus include foscarnet (U.S. Pat. No. 4,215,113); stannous salt, such as stannous fluroide (U.S. Pat. No. 5,098,716); and sulphated polysaccharides, such as dextran sulphate and pentosan polysulphate. Recently, U.S. Pat. No. RE37,727 discloses a method for treating nerves injury pain associated with shingles by using a local anethetic agent, lidocaine.
NSAIDs are not widely known for treatment of viruses, notwithstanding herpes viruses. U.S. Pat. Nos. 4,473,584 and 4,477,468 disclose a process for treating HSV1 and HSV2 infection by systemic administration or topical application of flurbiprofen (3-fluoro-4-phenylhydratropic acid) or a salt or ester thereof. U.S. Pat. No. 5,514,667 discloses a topical preparation for treating herpes virus infections which combines an anti-viral drug, such as foscarnet, suramin, polysulphated polysaccharides, polysulphated polymers, purine nucleoside analogues, with a potentiating drug which can be an NSAID. U.S. Pat. No. 5,747,070 discloses a treatment for herpes infections which combines stannous salt with another therapeutic agent, such as an NSAID.
The present invention provides a topical formulation containing an NSAID, preferably diclofenac, to provide fast and effective treatment for alleviating symptoms relating to HSV and VZV infections, including inflammation and/or pain caused by HSV and VZV infections. In comparing with the topical treatment by acyclovir, the topical formulation of the present invention reduces the recovery time from about two (2) weeks when acyclovir is applied, to about one (1) week when a topical preparation using the topical formulation of the present invention is applied.